The candidate is a Developmental Biologist with 25 years of experience in Reproductive Toxicology, Teratology and recently in Reproductive Epidemiology. The application describes a 3 year comprehensive, interdisciplinary program that will provide the candidate with the formal training and research experience necessary for her development as an independent investigator in Molecular Epidemiology of Birth Defects. The candidate's long-term career goal is to develop an academic program of research and teaching that combines molecular, genetic and epidemiologic methods to study the complex relationships of genes and environmental factors in the etiology of birth defects. The environment at the University of Pennsylvania is ideal for carrying out the research and training. There is a well-established history at this site for studying genetic risk factors for human disease, and there is a rich source of case and control infants for the proposed study in the Pediatric Urology Division of The Children's Hospital of Philadelphia. The training component includes mentorship by a Molecular Epidemiologist, a Genetic Epidemiologist and Reproductive Endocrinologist and completion of advanced courses in Genetic Epidemiology, Molecular Biology and Human Genetics. The research component describes a case-control study of the Molecular Epidemiology of Hypospadias in which gene by environment interactions are examined to understand risk factors for this birth defect. A doubling in the birth prevalence of mild and severe forms of hypospadias has recently been identified in the United States. Concern has focused on whether exposure to endocrine disrupting chemicals (EDCs) with anti-androgenic activity is the cause of this increase. The hypothesis of the proposed research study is that allelic variants in the steroid 5-alpha reductase type 2 (SRD5A2) gene (susceptible genotype) resulting in decreased 5 alpha reductase enzyme activity will be highly associated with the risk for and severity of hypospadias in male infants. It is further hypothesized that exposure to anti-androgenic agents during pregnancy may further increase the risk for hypospadias in infants with a susceptible genotype, resulting in a gene by environment interaction. The association between allelic variants in the SRD5A2 gene and hypospadias has only been evaluated to date in inbred families from geographically isolated areas. Results from these studies indicate at SRD5A2 enzyme activity is critical in formation of the external male genital tract, and dihydrotestosterone produced by this enzyme is essential for normal development of the penis, scrotum and prostate. This will be the first study in a large, outbred population to investigate the association between allelic variants in the SRD5A2 gene and environmental exposures on the risk for hypospadias. Expected results from this study are identification of individuals with the greatest susceptibility to developing hypospadias with exposure to EDCs, and evaluation of the relative contributions of genetic and environmental risk factors to the occurrence of this birth defect. The research proposal is an extension of the training component and exemplifies how molecular, genetic and epidemiologic approaches can be combined to study the etiology of birth defects.